Palladium-Catalyzed Inter- and Intramolecular α-Arylation of Amides. Application of Intramolecular Amide Arylation to the Synthesis of Oxindoles

Article abstract of DOI:10.1021/jo980611y

2A palladium-catalyzed α-arylation of amides is reported. Intermolecular arylation of N,N-dimethylamides and lactams occurs using aryl halides, silylamide base, and a palladium catalyst. Intramolecular arylation of N-(2-halophenyl)amides occurs using alkoxide base and a palladium catalyst. The palladium catalyst was formed in situ from Pd(dba)₂ (dba = trans,trans-dibenzylidene acetone) and BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthalene). Although the intermolecular arylation of amides is less general than that reported previously for ketones, unfunctionalized and electron-rich aryl halides gave α-arylamides in 48-75% yield and N-methyl-α-phenylpyrrolidinone in 49% yield. These reactions provided the highest yields yet reported for regioselective amide arylations. Intramolecular amide arylation of 2-bromoanilides gave oxindoles in 52-82% yield. Mono- and disubstituted acetanilides gave 1,3-di- and 1,3,3-trisubstituted oxindoles. The use of dioxane, rather than THF, solvent was important for some of the amide arylations.

Full text of DOI:10.1021/jo980611y

6546
J . Org. Chem. 1998, 63, 6546-6553
P a lla d iu m -Ca ta lyzed In ter - a n d In tr a m olecu la r r-Ar yla tion of
Am id es. Ap p lica tion of In tr a m olecu la r Am id e Ar yla tion to th e
Syn th esis of Oxin d oles
Kevin H. Shaughnessy, Blake C. Hamann, and J ohn F. Hartwig*
Department of Chemistry, Yale University, P.O. Box 208107, New Haven, Connecticut 06520-8107
Received April 3, 1998
2A palladium-catalyzed R-arylation of amides is reported. Intermolecular arylation of N,N-
dimethylamides and lactams occurs using aryl halides, silylamide base, and a palladium catalyst.
Intramolecular arylation of N-(2-halophenyl)amides occurs using alkoxide base and a palladium
catalyst. The palladium catalyst was formed in situ from Pd(dba)2 (dba ) trans,trans-dibenzylidene
acetone) and BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthalene). Although the intermolecular
arylation of amides is less general than that reported previously for ketones, unfunctionalized and
electron-rich aryl halides gave R-arylamides in 48-75% yield and N-methyl-R-phenylpyrrolidinone
in 49% yield. These reactions provided the highest yields yet reported for regioselective amide
arylations. Intramolecular amide arylation of 2-bromoanilides gave oxindoles in 52-82% yield.
Mono- and disubstituted acetanilides gave 1,3-di- and 1,3,3-trisubstituted oxindoles. The use of
dioxane, rather than THF, solvent was important for some of the amide arylations.
In tr od u ction
arylations, we have begun to explore the arylation of
other substrates such as carboxylic acid derivatives.
Palladium-catalyzed couplings of aryl and vinyl halides
or pseudohalides with organometallic reagents are widely
used in modern synthetic organic chemistry.1 Despite
the wide variety of organometallic reagents which medi-
ate these types of cross coupling reactions, examples of
enolate additions to aryl and vinyl halides have been
limited in scope.2-15 Only recently have reports by us,16
Buchwald,17,18 and Satoh19 shown that the palladium-
catalyzed, intermolecular coupling of aryl halides and
ketone enolates is a useful methodology for the synthesis
of R-aryl ketones. On the basis of our success with ketone
R-Arylamides have potential medical and agricultural
applications, but few general methods for their prepara-
tion have been reported. Classical methods for the amide
R-arylation have involved Friedel-Crafts or photoiniti-
ated addition of R-haloamides to arenes.20 These reac-
tions give poor regioselectivity and variable yields.
Enolates formed from N-methylpyrrolidinone (NMP)
have been coupled with aryl halides to give 3-arylpyrro-
lidinones in low to moderate yields (15-50%) in the
presence of an excess of strong base.21 Since this reaction
occurs through a benzyne intermediate, addition to
substituted arenes often gives mixtures of regioisomers.
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Synthesis (Comprehensive Organometallic Chemistry); Hegedus, L. S.,
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1
mechanism initiated photochemically was the first and
only reported example of a regioselective amide aryla-
tion.22,23 However, this methodology required enolate to
aryl halide ratios of 15:1 to achieve > 2:1 mono:diaryla-
tion selectivities. In view of the limited number of
methodologies for the selective arylation of amides, we
have explored the extension of the palladium-catalyzed
ketone arylation methodology to amide arylation.
Oxindoles are important substructures in numerous
biologically active molecules.24 Considering the potential
to conduct intermolecular amide arylations, it seemed
likely that an intramolecular variant of the amide
arylation could be developed for oxindole syntheses. A
number of methods for the synthesis of oxindole com-
pounds have been reported. Friedel-Crafts cyclizations
of R-haloacetanilides and variations on the Fischer indole
synthesis are the classical methods of oxindole synthe-
sis.25 Cyclizations of 2-haloacryloylanilide derivatives by
a variety of radical initiators have been reported more
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53, 4149-4151.
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12382-12383.
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J . Org. Chem. 1987, 52, 2110-2113.
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11108-11109.
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wald, S. J . Am. Chem. Soc. 1998, 120, 1918-1919.
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Chem., Int. Ed Engl. 1997, 36, 1740-1742.
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1993, 130, 111-116.
(24) See footnotes 2 and 3 in Goehring et al., ref 38.
S0022-3263(98)00611-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/02/1998

Pd-Catalyzed R-Arylation of Amides
J . Org. Chem., Vol. 63, No. 19, 1998 6547
recently.26-31 Metal-catalyzed routes to oxindoles include
cyclocarbonylations of 2-aminostyrenes catalyzed by pal-
ladium,32 rhodium catalyzed carbonylations of 2-alkynyl-
anilines,33 rhodium- and Nafion-H-catalyzed cyclizations
of R-diazoamides,34,35 and intramolecular Heck couplings
of 2-haloacryloylanilides.36,37 Photochemical,38,39 Ullman-
type,40 and radical41 promoted cyclizations of saturated
2-haloanilide derivatives have also been reported.
Although there are a variety of methods for synthesiz-
ing these structures, methods which form oxindoles with
complete regioselectivity are rare. Friedel-Crafts meth-
ods and more recent variations do not allow control of
arene regiochemistry.25,40,41 Most other methodologies
involve cyclization by addition of reactive intermediates
to olefin or alkynyl moieties. Often these additions occur
with poor regioselectivity producing mixtures of oxindole
and 3,4-dihydroquinolin-2-one products.26,28-31,33,36 Re-
gioselectivity becomes particularly poor when attempting
to prepare 3,3-disubstituted oxindoles. Preparation of
oxindoles via intramolecular amide arylation of 2-haloa-
nilide substrates would be expected to occur with com-
plete regioselectivity regardless of the substrate’s sub-
stitution pattern.
Ta ble 1. Op tim iza tion of Liga n d , Ba se, a n d Solven t in
Am id e Ar yla tion a
yield of
2a b
yield of
4a b
entry
ligand
base
solvent
%
%
1
2
3
4
5
DPPF
BINAP
DPPF
DPPF
DPPF
KHMDS
KHMDS
LiTMP
KHMDS
LiTMP
THF
THF
THF
dioxane
dioxane
22
32
5
48
38
22
8
4
2
5
a
Reactions run with 0.1 mmol of substrate, 7.5 mol % of
b
Pd(OAc)2, 9% ligand, 1.2 equiv of base at 85 °C for 2 h. Yields
determined by GC.
with N,N-dialkylamides in the presence of an excess
amount of potassium hexamethyldisilazide (KHMDS)
and a catalytic amount of Pd(dba)2 and chelating phos-
phine ligand (eq 1). A series of reactions carried out on
Although extension of the palladium-catalyzed ketone
arylation methodology to the arylation of amides ap-
peared conceptually simple, the significantly higher pKa
of amides compared to that of ketones appears to affect
the rate of many of the steps of the catalytic cycle. Thus,
it was necessary to find modified reaction conditions for
both inter- and intramolecular amide arylation. Herein,
we report the first example of a palladium-catalyzed,
intermolecular arylation of dialkylamides and pyrrolidi-
nones, along with intramolecular versions of this reaction
that produce oxindoles.
a 0.10 mmol scale were used to determine a suitable
ligand, base, and solvent for the amide arylation reaction.
Use of either DPPF or rac-BINAP42 resulted in an active
catalyst system. BINAP gave higher yields of arylated
amide (Table 1, entries 1-2). Other chelating phos-
phines such as bis(di-o-tolylphosphino)ferrocene (DTPF),
which was effective in ketone arylations, and bis(diphen-
ylphosphino)xanthene produced catalysts with low activ-
ity for the amide arylation reaction. We do not under-
stand the difference between the activity of DTPF-ligated
palladium in the ketone and amide arylations.
KHMDS was the most effective base for the amide
arylation. Reactions employing KHMDS gave signifi-
cantly higher yields than did reactions run with lithium
tetramethylpiperidine (LiTMP) (Table 1, entries 2-5).
Use of sodium tert-butoxide resulted in very slow conver-
sion and high levels of undesired side products, while
lithium diisopropylamide appeared to deactivate the
catalyst system. THF and dioxane were suitable solvents
for amide arylation, but reactions in dioxane consistently
gave higher yields than those for reactions in THF.
Using BINAP as ligand, KHMDS as base, and dioxane
as solvent, a series of preparative scale reactions were
conducted. The coupling of 2-bromonaphthalene (1b)
with N,N-dimethylacetamide (DMA) using palladium
acetate as metal source gave coupled product 2b in 44%
yield (eq 1, Table 2, entry 2). Use of Pd(dba)2, rather
than Pd(OAc)2, under identical conditions gave 2b in 57%
yield (Table 2, entry 1). Arene (4b) formed from hydro-
dehalogenation of the aryl halide was a common side
product in the arylation chemistry. The amount of this
side product was essentially unchanged between these
two reactions, but the amount of product resulting from
amide cleavage to form amine followed by aryl halide
Resu lts
In ter m olecu la r Ar yla tion of N,N-Dia lk yla m id es.
In a simple, one-pot procedure, aryl halides were coupled
(25) Beckett, A. H.; Daisley, R. W.; Walker, J . Tetrahedron 1968,
24, 6093-6109 and references therein.
(26) J ones, K.; Thompson, M.; Wright, C. J . Chem. Soc., Chem.
Commun. 1986, 115-116.
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1988, 29, 6657-6660.
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(29) J ones, K.; Wilkinson, J .; Ewin, R. Tetrahedron Lett. 1994, 35,
7673-7676.
(30) Clark, A. J .; Davies, D. I.; J ones, K.; Millbanks, C. J . Chem.
Soc., Chem. Commun. 1994, 41-42.
(31) Cabri, W.; Candiani, I.; Colombo, M.; Franzoi, L.; Bedeschi, A.
Tetrahedron Lett. 1995, 36, 949-952.
(32) Ali, B. E.; Okuro, K.; Vasapollo, G.; Alper, H. J . Am. Chem.
Soc. 1996, 118, 4264-4270.
(33) Hirao, K.; Morii, N.; J oh, T.; Takahashi, S. Tetrahedron Lett.
1995, 35, 6243-6246.
(34) Doyle, M. P.; Shanklin, M. S.; Pho, H. Q.; Mahapatro, S. N. J .
Org. Chem. 1988, 53, 1017-1022.
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Marino, J . P., J r.; Padwa, A. J . Org. Chem. 1994, 59, 2447-2455.
(36) (a) Mori, M.; Ban, Y. Tetrahedron Lett. 1976, 1807-1810. (b)
Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J . J . Am. Chem.
Soc. 1998, 120, 6477-6487. (c) Ashimori, A.; Bachand, B.; Calter, M.
A.; Govek, S. P.; Overman, L. E.; Poon, D. J . J . Am. Chem. Soc. 1998,
120, 6488-6499 and references therein.
(37) For an example in solid phase organic synthesis see: Aru-
mugam, V.; Routledge, A.; Abell, C.; Balasubramanian, S. Tetrahedron
Lett. 1997, 38, 6473-6476.
(38) Goehring, R. R.; Sachdeva, Y. P.; Pisipata, J . S.; Sleevi, M. C.;
Wolfe, J . F. J . Am. Chem. Soc. 1985, 107, 435-443.
(39) Wolfe, J . F.; Sleevi, M. C.; Goehring, R. J . Am. Chem. Soc. 1980,
102, 3646-3647.
(40) Kametani, T.; Ohsawa, T.; Ihara, M. Heterocycles 1980, 14,
277-280.
(41) Beckwith, A. L. J .; Storey, J . M. D. J . Chem. Soc., Chem.
Commun. 1995, 977-978.
(42) DPPF ) 1,1′-bis(diphenylphosphino)ferrocene. rac-BINAP )
rac- 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene.

6548 J . Org. Chem., Vol. 63, No. 19, 1998
Shaughnessy et al.
Ta ble 2. Effect of P d Sou r ce a n d Rea ction
Con cen tr a tion on Ar yla m id e Yield a
Ta ble 3. In ter m olecu la r Ar yla tion of N,N-Dia lk yla m id es
yield of yield of yield of yield of
entry Pd source [1b], M 2bb
%
3bb
%
4bb
%
5bb
%
1
2
3
4
5
Pd(dba)2
Pd(OAc)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
0.45
0.45
0.10
0.01
0.10
57
44
70
75
n.d.d
n.d.
9
n.d.
24
(5)
(6)
(5)
(3)
(1)
(7)
(1)
(1)
52c
n.d.
n.d.
a
Reactions run with 2 mmol of substrate, 5% Pd, 7.5% BINAP,
b
2 equiv of KHMDS, in dioxane at 100 °C for 2 h. Isolated yields
except those in parentheses which indicate GC yields. c 1.5 equiv
d
of KHMDS. n.d. ) not determined.
amination was different. The palladium acetate-cata-
lyzed reaction gave a significantly higher amount of
dimethylaminonaphthalene (7% vs 1%).
Reaction concentration and quantity of base also
appeared to affect the reaction yields. Decreasing the
reaction concentration from [ArBr] ) 0.45 to 0.10 M
resulted in an increase in the yield from 57% to 70%
(Table 2, entries 1 and 3), while a further decrease in
the reaction concentration to 0.01 M gave 2b in 75% yield
(Table 2, entry 4). The use of at least 2 equiv of base
was necessary for good yields. Reactions employing 1.5
equiv of base resulted in only 52% yield of 2b, and these
conditions led to formation of diarylated product in 24%
yield (Table 2, entry 5). Thus, it was important to use 2
equiv of base in order to conduct selective monoarylations
of DMA. Increasing the amount of DMA eliminated the
formation of diarylated product but had no effect on the
yield of monoarylamide.
A variety of aryl halides were, therefore, coupled with
DMA using 5 mol % Pd(dba)2, 7.5 mol % BINAP, and 2
equiv of KHMDS at 0.10 M concentration in dioxane at
95-100 °C as shown in eq 1 and Table 3. Arenes 1b-d
gave good yields of the desired R-arylacetamides (66-
72%). Undesired side products were principally diary-
lated amides (3b-d ) formed in approximately 10% yield,
along with arenes 4b-d (5%) and dimethylaminoarenes
5b-d (1%). The dimethylaminoarene side products
formed from reactions using substrates 1c and 1d were
observed as 1:1 mixtures of two isomers. Although
dimethylaminoarenes are minor side products, their
formation and reactivity are interesting. The 1:1 mixture
of isomers in this case and others presented below shows
that the aminoarenes are not formed by the palladium-
catalyzed amination of aryl halide, which is regio-
specific.43-45 Rather, the aminoarene more likely forms
through the trapping of an aryne species by dimethy-
lamine, presumably formed in the reaction mixture
through transamination of DMA with KHMDS.
a
Yields are isolated yields for the average of at least two
independent runs. Yields in parentheses are GC yields. All isolated
products were fully characterized spectroscopically (1H and 13C
NMR, FTIR, and LRMS) and are consistent with previously
reported values. 0.5 equiv of DMA used. c 4,4′-dimethylbiphenyl
b
observed in 13% yield by GC. P(t-Bu)3 used as ligand. e Butyl-
d
benzene was produced in 78% yield by GC.
lated amide 3d in 74% yield and the monoarylated
product 2d in 24% yield.
Methoxy-substituted bromoarene 1f gave R-arylaceta-
mide 2f in lower yield (48%) and produced larger amounts
of diarylated product (18%), arene (13% by GC), and
dimethyaminoarene (16% by GC) (Table 3, entry 7).
Again, dimethylaminoanisole was observed as a 1:1
mixture of isomers. Electron-poor arene 1g (eq 1) gave
only trace amounts of R-aryl amide under the standard
reaction conditions. The major products identified by
GCMS were trifluoromethyl-N,N-dimethylaniline and
trifluoromethyl-N,N-bis(trimethylsilyl)aniline, which were
produced in approximately a 1:1 ratio (20% combined
yield by GC). Both aminated products were observed as
1:1 mixtures of isomers by GC. Electron-deficient arenes
such as 4-bromobenzonitrile reacted directly with KH-
MDS. Attempts to carry out the amide arylation using
the weaker base sodium tert-butoxide resulted in a 57%
yield of 4-tert-butoxybenzonitrile, which has been shown
previously to form from palladium-catalyzed conversion
of the aryl halide to an aryl ether.46,47
The sterically hindered 2-bromotoluene (1e) gave a
72% yield of arylamide 2e. This yield is identical to that
observed with the unhindered substrate 4-bromotoluene.
However, the amount of diarylated product was reduced
to 4%. Iodotoluene reacted with DMA to give 2d in 70%
yield (Table 3, entry 5). 4,4′-Dimethylbiphenyl was
observed as the major side product (13%) from this
reaction, while the diarylated product was produced in
only 4% yield. Coupling of 1d with 0.5 equiv of DMA
using 1.25 equiv of KHMDS per aryl halide gave diary-
Attempted arylation of N,N-dimethylpropionamide
(DMP) with 4-bromotoluene under the standard condi-
tions resulted principally in the reduction of the aryl
halide to toluene. Use of tri(o-tolyl)phosphine in place
of BINAP gave similar results. Coupling of 4-bromo-
butylbenzene with DMP using tri(tert-butyl)phosphine as
(43) Louie, J .; Hartwig, J . Tetrahedron Lett. 1995, 36, 3609-3612.
(44) Wolfe, J . P.; Wagaw, S.; Buchwald, S. L. J . Am. Chem. Soc.
1996, 118, 7215-7216.
(45) Driver, M. S.; Hartwig, J . F. J . Am. Chem. Soc. 1996, 118,
7217-7218.
(46) Mann, G.; Hartwig, J . J . Am. Chem. Soc. 1996, 118, 13109-
13110.
(47) Palucki, M.; Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc.
1997, 119, 3395-3396.

Pd-Catalyzed R-Arylation of Amides
J . Org. Chem., Vol. 63, No. 19, 1998 6549
Ta ble 4. Op tim iza tion of In tr a m olecu la r Am id e r-Ar yla tion a
yield of
10b
yield of
entry
ligand
base
solvent
temp, °C
time, h
convn.b %
%
11b
%
1
2
3
4
5
6
7
8
9
DPPF
DPPF
BINAP
DPPF
BINAP
DPPF
BINAP
DPPF
P(o-tol)3
BINAP
KHMDS
THF
THF
THF
dioxane
dioxane
THF
75
75
75
75
75
100
100
100
100
100
19
19
23
23
23
3
3
3
4
3
100
100
85
40
95
96
100
96
18
100
trace
56
65
10
50
53
57
43
6
14c
13
2
1
1
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
9
2
THF
dioxane
dioxane
dioxane
10
n.d.d
1
10
64
a
Reactions run with 3.5 µmol of Pd(dba)2, 5.3 µmol of ligand, 105 µmol of base, and 70 µmol of substrate in 1.5 mL of solvent at the
indicated temperature. Reaction yields determined by GC. c Also observed N-benzylaniline (40%). Not detected.
b
d
Ta ble 5. F or m a tion of Oxin d oles fr om 2-Br om oa n ilid es
ligand gave 2-(4-butylbenzene)propionamide 6 in 16%
yield and butylbenzene in 78% yield as determined by
GC (Table 3, entry 8). Attempted arylation of N,N-
dimethylisobutyramide resulted exclusively in hydrode-
halogenation of the aryl halide.
Arylations of lactams such as NMP were more suc-
cessful than arylations of secondary carbon sites in acyclic
amides. For example, bromobenzene reacted with NMP
to give the arylation product 7 in 49% yield (Table 3,
entry 9). The diarylation product diphenylpyrrolidinone
8 was formed competitively in 9% yield. Although the
yield is lower than that for DMA, this reaction yield is
comparable to the only other reported synthesis of
3-arylpyrrolidinones, and the previous method provided
regioisomeric mixtures of products for reactions con-
ducted with substituted arenes.21
Oxin d ole Syn th esis via In tr a m olecu la r Am id e
Ar yla tion . The ability to conduct intermolecular R-ary-
lation of amides led us to investigate an intramolecular
variant of this reaction that would generate oxindoles.
We investigated the use of 2-bromoanilides as substrates
for cyclization to oxindoles. N-(2-Bromophenyl)-N-alky-
lamides are readily prepared by coupling 2-bromoaniline
to an acid chloride followed by N-alkylation of the
resulting amide. Treatment of N-benzyl-2-bromoaceta-
nilide (9) with sodium tert-butoxide (1.5 equiv) in the
presence of Pd(dba)2 (5 mol %) and a chelating phosphine
such as BINAP or DPPF resulted in the formation of
1-benzyloxindole 10 in up to 66% yield (eq 2, Table 5,
entry 2).
a
b
Reaction times were not optimized. Isolated yields from the
average of at least two runs. All compounds were fully character-
ized spectroscopically (1H and 13C NMR, FTIR, and LRMS) and
are consistent with previously reported values. c Reduced arene
d
yields determined by GC. 10 mol % of Pd used.
Reactions run with BINAP typically gave higher yields
than those run with DPPF or P(o-tolyl)3 (Table 4). Only
trace amounts of hydrodehalogenation product were
observed in reactions employing BINAP. When DPPF
was used as ligand, 10 was observed in 40-50% yield,
along with hydrodehalogenation product 11 that was
formed in approximately 10% yield. The use of tri(o-
tolyl)phosphine as ligand gave much lower yields. Only
18% conversion and 6% yield of oxindole 10 was observed
from reactions using this ligand. Reactions run at 75 °C
with BINAP as ligand required at least 19 h for complete
consumption of starting material, but reactions run at
100 °C provided complete reaction in less than 3 h
without decrease in the selectivity of the arylation
chemistry. Reactions run in dioxane solvent gave slightly
higher yields than those run in THF.
As was the case for intermolecular amide arylations,
the choice of base was important (Table 4). In this case,
reactions run with sodium tert-butoxide gave clean
conversion to the oxindole product with no side products
observed in the reaction mixture other than arene 11
from hydrodehalogenation. In contrast, reactions con-
ducted with KHMDS as the base resulted in significant
deacylation of the acetanilide substrate giving N-benzy-
laniline in approximately 40% yield and only a trace of
the desired oxindole 10. No conversion was observed for
reactions employing cesium carbonate as base.
In addition to N-benzyloxindole, cyclization to form
N-alkyl versions of the parent oxindole core occurred in

6550 J . Org. Chem., Vol. 63, No. 19, 1998
Shaughnessy et al.
Sch em e 1. P r op osed Mech a n ism of Am id e
En ola te Ar yla tion
strate 22 gave 5-methoxy-1,3,3-trimethyloxindole (23) in
80% yield. This cyclization of substrate 22 required 12
h, compared to the 4 h reaction time necessary for the
unsubstituted 18. Cyano-substituted substrate 24 also
underwent clean, high-yielding (83%) conversion to 5-cy-
ano-1,3,3-trimethyloxindole (25), but required 10 mol %
palladium catalyst for complete conversion. These re-
sults contrast those for our intermolecular amide aryla-
tion, in which both electron rich and electron poor
aromatic systems gave lower yields than those of electron
neutral systems.
Attempted intramolecular arylation to generate six-
membered rings has so far been unsuccessful. The
reaction of N-(2-bromobenzyl)amide 26 under the condi-
tions described above resulted in rapid consumption (<30
min) of the substrate but provided only 5% yield of the
isoquinolinone product 27 (eq 3). N-Benzylacetamide 28
(7%) was also observed by GC. Variation of reaction
temperature and concentration had little effect on the
yield of 27, and the fate of the remaining material has
not been determined.
good yields. The ability to produce 1-substituted oxin-
doles by this route avoids alkylation of oxindole that often
occurs with poor regioselectivity.48 1-Methyloxindole 13
was produced in 60% yield from N-methyl-2-bromoac-
etanilide (12) (Table 5, entry 1). However, the use of
N-methyl-2-iodoacetanilide (12-I) resulted in only a 40%
yield of 13 as determined by GC.
Substrates with secondary C-H bonds R to the carbo-
nyl also gave oxindole products. R-Arylacetanilide 14
was converted to the corresponding oxindole 15 in yields
comparable to those for unsubstituted substrates (Table
5, entry 3). However, this reaction was significantly
slower (10 h compared to 2-4 h) than arylation of the
alkyl-substituted substrates. Intramolecular amide ary-
lation of 16 gave oxindole 17 in a lower 52% yield with
an increase in the amount of hydrodehalogenation prod-
uct to 8% (Table 5, entry 4). Although the yield of this
cyclization was lower than that for unsubstituted and
disubstituted (see below) 2-bromoacetanilide substrates,
it was much higher than that observed for the intermo-
lecular R-arylation of DMP.
As noted in the Introduction, the importance of 3,3-
disubstituted oxindoles as pharmaceuticals makes the
development of new synthetic routes to this core impor-
tant. In contrast to the attempted intermolecular aryl-
ation of secondary and tertiary amide enolates, N-(2-
bromophenyl)isobutyramide 18 underwent clean intra-
molecular arylation to form 1,3,3-trimethyloxindole in
75% yield. The spirocyclic oxindole 21 was also produced
in excellent yield (82%). These reactions demonstrate
that the intramolecular amide arylation should be a
useful methodology for generating this type of core in
biologically active oxindoles.
Discu ssion
We have now extended the palladium-catalyzed inter-
molecular arylation of ketone enolates developed by us16
and Buchwald17,18 to the arylation of amides. While little
mechanistic work has been conducted on the amide
arylation at this time, we propose that the reaction occurs
by the catalytic cycle shown in Scheme 1 in analogy to
proposed catalytic cycles for ketone arylation16,17 and
experimentally verified cycles in the related amination
chemistry.43-45 Oxidative addition of aryl halide to
palladium(0) complex 29 would give arylpalladium halide
complex 30. Addition of the amide enolate would form
arylpalladium enolate complex 31, which could reduc-
tively eliminate product. By using the less acidic amide
in place of ketones, the rates of palladium enolate
formation, R-aryl amide formation by reductive elimina-
tion, and arene formation by â-hydride elimination from
the palladium enolate will be altered. The cumulative
effect of these changes on the relative rates for different
steps of this cycle are difficult to predict. Thus, we
conducted a series exploratory synthetic experiments to
find conditions for the use of amides as substrates.
Several aspects of the reaction conditions and types of
reaction products warrant discussion.
First, the selection and quantity of base was crucial to
obtaining good reaction yields. The higher pKa of amides
apparently makes the use of the strong base KHMDS
necessary. Two equivalents of base are presumably
required to deprotonate both the substrate amide and the
more acidic monoarylamide product (eq 4). In the
absence of a second equivalent of base, the concentration
of enolate 32a becomes low since the pKa of the amide
corresponding to enolate 32a is approximately 9 pKa units
higher than that of the product amide corresponding to
Both electron-withdrawing and electron-donating sub-
stituents are tolerated on the aromatic ring of the
2-bromoanilide substrate. Methoxy-substituted sub-
(48) Kende, A. S.; Hodges, J . C. Synth. Comm. 1982, 12, 1-10 and
references therein.

Pd-Catalyzed R-Arylation of Amides
J . Org. Chem., Vol. 63, No. 19, 1998 6551
enolate 33a (33.5 vs 24.5 in THF).49 Thus, the slower
arylation of product enolate 33a becomes a competitive
pathway when 1 equiv of base is used.
F igu r e 1. Examples of simple, biologically active compounds
with 3,3′-disubstituted oxindole cores.
In contrast to the requirement of 2 equiv of base in
the amide arylations, 1.2 equiv of base was used in the
ketone arylations.16,17 The pKas of R-aryl ketones (33b)
and alkyl ketones (32b) are lower and more similar to
each other than those of the corresponding amides (pKas
of 32b and 33b ) 24.7 and 17.65 in DMSO, respec-
tively).50 The greater selectivity for monoarylation of
ketones may therefore be due to the higher relative
concentration of 32b in the equilibrium mixture com-
pared to 32a . It also is possible that 33b undergoes
arylation very slowly due to its more highly stabilized
anion.
Enolate stability also seems to control reaction rates
for the intramolecular arylations. The slower conversion
of the phenyl-substituted substrate 14 (Table 5, entry 3)
appears to result from the amide pKa rather than from
steric factors, considering that the disubstituted sub-
strates 18 and 20 underwent ring closure at approxi-
mately the same rate as the unsubstituted substrates.
Interestingly, the intramolecular arylation of an R-ary-
lamide takes approximately twice as long as the inter-
molecular arylation of an R-arylamide. For example, 3d
was produced in approximately 4 h in the reaction of 1d
with 0.5 equiv of DMA, while cyclization of 14 required
10 h.
Attempts to arylate homologous amides such as DMP
under our standard conditions resulted in the formation
of trace amounts of desired R-arylamide plus numerous
side products. Bulky monophosphines such as tri(o-
tolyl)phosphine and tri(tert-butyl)phosphine gave high
yields in the coupling of secondary amines and aryl
halides.43,45 Considering the similar steric demand and
basicity of secondary amines and secondary amide enol-
ates, one might have expected these ligands to provide
improved, or at least competitive, yields in comparison
to those obtained using chelating phosphines. However,
tri(o-tolyl)phosphine gave a short-lived, inactive catalyst
and tri(tert-butyl)phosphine gave low yields of R-aryl
amides. Clearly our understanding of the factors govern-
ing this reaction at this time are not sufficient to
rationally select or design ligands for this process.
Perhaps the most synthetically valuable amide aryla-
tion is the formation of 3,3-disubstituted oxindole cores.
In contrast to the intermolecular amide arylation of R,R-
disubstituted substrates, which occurred in low yields,
the intramolecular arylation of R,R-disubstituted sub-
strates occurred in the highest yields. The ability to
cleanly produce 3,3-disubstituted oxindoles is significant
due to the difficulty in preparing these structures by
other methods and the importance of 3,3-disubstituted
oxindoles as biologically active compounds. Examples of
biologically active 3,3-disubstituted oxindoles that may
be accessible by this methodology are horsfiline (34),51
vasopressin binder 35,52 and compound 36 which has
been proposed as a treatment of cognitive or neurological
dysfunction (Figure 1).53
Con clu sion
Palladium-catalyzed coupling of unfunctionalized aryl
halides and DMA is a simple and efficient synthesis of
R-arylamides. Unlike the analogous ketone arylation,
amide arylation was less effective with homologous
amides. Reactions of electron-deficient arenes gave
products from nucleophilic attack by base, while electron-
rich arenes gave moderate yields of arylamide. Although
the intermolecular reaction was somewhat limited in
scope, it still represents the most selective and general
method yet reported for the direct arylation of alkyla-
mides.
Intramolecular amide arylation of 2-haloanilides now
represents a versatile methodology for preparing substi-
tuted oxindoles. The intramolecular reaction was sig-
nificantly more tolerant of both electronic and steric
modifications of the substrate than was the intermolecu-
lar reaction. Particularly significant was the ability to
prepare 3,3-disubstituted oxindoles in high yield with
complete regioselectivity. This methodology should prove
useful in the synthesis of biologically interesting oxindole
structures.
Exp er im en ta l Section
Gen er a l Con sid er a tion s. All coupling reactions were set
up in a nitrogen drybox and run in sealed reaction flasks under
a nitrogen atmosphere. Pd(dba)2 was prepared by a literature
procedure.54 BINAP, DPPF, tri(o-tolyl)phosphine, tri(tert-
butyl)phosphine, KHMDS, NaO-t-Bu, aryl halides, N,N-di-
methylamides, and NMP were obtained from commercial
sources and used as received. THF was distilled from sodium/
benzophenone. Anhydrous grade dioxane was purchased from
Aldrich and was used and stored in a nitrogen glovebox.
2-Bromoanilide substrates for oxindole synthesis (9, 12, 14,
16, 18, 20, 22, 24) were prepared from 2-bromoanilines by
coupling to the appropriate acid chloride followed by N-
alkylation of the resulting amide. 4-Amino-3-bromoanisole
was prepared from 3-bromophenol by literature methods.55,56
4-Amino-3-bromobenzonitrile was prepared by the previously
(51) J ossang, A.; J osssang, P.; Hadi, H. A.; Se´venet, T.; Bodo, B. J .
Org. Chem. 1991, 56, 6527-6530.
(52) Foulon, L.; Garcia, G.; Misato, D.; Roux, R.; Seradeil-Legal, C.;
Valette, G.; Wagnon, J . WO 15, 051, 1993.
(53) Wilkerson, W.; Wilkie, E.; Richard, A.; Voss, M. E. WO 14, 085,
1993.
(54) Rettig, M. F.; Maitlis, P. M. Inorg. Synth. 28, 110-111.
(55) Hodgson, H. H.; Moore, F. H. J . Chem. Soc. 1926, 128, 155-
161.
(56) Frank, H. R.; Fanta, P. E.; Tarbell, D. S. J . Am. Chem. Soc.
1948, 70, 2314-2320.
(49) Krom, J . A.; Streitwieser, A. J . Org. Chem. 1996, 61, 6354-
6359.
(50) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463.

6552 J . Org. Chem., Vol. 63, No. 19, 1998
Shaughnessy et al.
reported bromination of 4-aminobenzonitrile.57 Naphthalene
was used as a standard in quantitative GC experiments using
response factors determined from isolated products. 1H and
13C NMR data are reported in ppm from TMS and were
referenced to residual solvent protons or internal TMS. Low-
resolution mass spectral data was obtained on a Hewlett-
Packard 5890 series II gas chromatograph interfaced with a
Hewlett-Packard 5989 A mass spectrometer. Electron impact
ionization was used for all samples. Elemental analyses were
performed by Robertson Microlit Laboratories, Inc., Madison,
NJ .
Gen er a l P r oced u r e for In t er m olecu la r Ar yla t ion of
Am id es. In the drybox, Pd(dba)2 (57.5 mg, 0.10 mmol), BINAP
(93.4 mg, 0.15 mmol), and KHMDS (796 mg, 4.00 mmol) were
combined in a small round-bottom flask followed by addition
of 18 mL of dioxane. Aryl halide (2.00 mmol) and amide (2.15
mmol) were then added, and the flask was sealed with a
septum. The reaction flask was placed in an oil bath preheated
to 100 °C. Once the aryl halide was completely consumed as
determined by GC, the reaction mixture was poured into 50
mL of saturated NH4Cl solution and extracted 3 × 30 mL with
ether. The combined ether extracts were washed with brine
(50 mL), dried over MgSO4, and filtered. The solvent was
removed under vacuum, and the resulting crude oil was flash
chromatographed on silica gel. The product was eluted with
a 15-45% solvent gradient of ethyl acetate in hexanes (200
mL, 15% increments).
mL, 1.00 mmol) to give 2d (85 mg, 24%) and 3d (139 mg, 52%)
as a pale yellow, waxy solid after chromatography. 1H NMR
(300 MHz, CDCl3): 7.12 (brs, 8H), 5.14 (s, 1H), 2.99 (s, 3H),
2.98 (s, 3H), 2.30 (s, 6H) ppm. 13C NMR (125 MHz, CDCl3):
171.9, 136.7, 136.3, 129.0, 129.0, 53.9, 37.4, 35.9, 2089 ppm.
MS (EI): 267 m/z.
N,N-Dim eth yl-2-(2-tolyl)a ceta m id e (2e).58 2-Bromotolu-
ene (0.24 mL, 2.00 mmol) and DMA (0.20 mL, 2.15 mmol) were
heated at 100 °C for 1.5 h to give 254 mg (72%) of 2e as a pale
yellow solid after chromatography. Recrystallization from
hexanes gave fine, colorless needles (mp 53-54 °C, Lit mp 54-
55 °C). 1H NMR (300 MHz, CDCl3): 7.16-7.11 (m, 4H), 3.66
(s, 2H), 2.99 (s, 3H), 2.98 (s, 3H), 2.27 (s, 3H) ppm. 13C NMR
(125 MHz, CDCl3): 170.8, 136.3, 133.7, 130.1, 128.6, 126.7,
126.0, 38.4, 37.4, 35.4, 19.5 ppm. FTIR (KBr pellet): 1640
cm-1. Anal. Calcd for C11H15NO: C, 74.54; H, 8.53; N, 7.90.
Found: C, 74.51; H, 8.37; N, 7.95.
N,N-Dim et h yl-2-(4-m et h oxyp h en yl)a cet a m id e (2f).23
4-Bromoanisole (0.24 mL, 0.20 mmol) was coupled with DMA
(0.20 mL, 2.15 mmol) at 100 °C for 4 h to give 186 mg (50%)
of 2f as a pale yellow oil after chromatography. 1H NMR (300
MHz, CDCl3): 7.17 (d, J ) 8.55 Hz, 2H), 6.85 (d, J ) 8.58 Hz,
2H), 3.78 (s, 3H), 3.65 (s, 3H), 2.99 (s, 3H), 2.95 (s, 3H) ppm.
13C NMR (125 MHz, CDCl3): 171.3, 158.3, 129.7, 127.0, 114.0,
55.3, 40.0, 37.6, 35.5 ppm. FTIR (neat, NaCl plate): 1642
cm-1
.
1-Meth yl-3-p h en ylp yr r olid in -2-on e (7).21 Bromobenzene
(0.21 mL, 1.99 mmol) and NMP (0.21 mL, 2.19 mmol) were
heated at 100 °C for 3 h to give 172 mg (49%) of 7 as a tan
solid after chromatography. 1H NMR (500 MHz, CDCl3):
7.34-7.29 (m, 2H), 7.27-7.22 (m, 3H), 3.64 (t, J ) 8.77 Hz,
1H), 3.48-3.38 (m, 2H), 2.93 (s, 3H), 2.54-2.48 (m, 1H), 2.15-
2.07 (m, 1H) ppm. 13C NMR (125 MHz, CDCl3): 174.8, 139.9,
128.6, 127.8, 126.8, 47.4, 47.6, 30.0, 27.9 ppm. FTIR (KBr
N,N-Dim et h yl-2-(2-n a p h t h yl)a cet a m id e (2b ). 2-Bro-
monaphthalene (420 mg, 2.03 mmol) was coupled with DMA
(0.20 mL, 2.15 mmol) at 100 °C for 2 h to give 305 mg (70%)
of 2b as a tan solid after chromatography. Recrystallization
from hexanes gave pale yellow needles (mp 93.5-94 °C). 1H
NMR (300 MHz, CDCl3): 7.82-7.77 (m, 3H), 7.69 (s, 1H),
7.46-7.26 (m, 3H), 3.88 (s, 2H), 3.01 (s, 3H), 2.99 (s, 3H) ppm.
13C NMR (125 MHz, CDCl3): 170.9, 133.5, 132.6, 132.3, 128.3,
127.6, 127.5, 127.1, 127.0, 126.0, 125.6, 41.2, 37.7, 35.6 ppm.
FTIR (KBr pellet): 1647 cm-1. Anal. Calcd for C14H15NO: C,
78.84; H, 7.09; N, 6.56. Found: C, 78.69; H, 6.94; N, 6.39.
N,N-Dim eth yl-2,2-d i(2-n a p h th yl)a ceta m id e (3b). This
material was isolated from an experiment conducted as
described above for 2b, but using only 3.00 mmol of KHMDS.
After chromatography, 3b (82 mg, 24%) was recovered as a
white solid (mp 159-161 °C). 1H NMR (500 MHz, CDCl3):
7.81-7.78 (m, 6 H), 7.72 (s, 2H), 7.45-7.42 (m, 6 H), 5.55 (s,
1H), 3.08 (s, 3H), 3.06 (s, 3H) ppm. 13C NMR (125 MHz,
CDCl3): 171.2, 137.0, 133.4, 132.5, 128.2, 127.9, 127.6, 127.5,
127.4, 126.0, 125.8, 55.1, 37.7, 36.1 ppm. MS (EI): 339 m/z.
N,N-Dim eth yl-2-(4-bip h en yl)a ceta m id e (2c).49 4-Bro-
mobiphenyl (470 mg, 2.02 mmol) was coupled with DMA (0.20
mL, 2.15 mmol) at 100 °C for 2 h to give 319 mg (66%) of 2c
as a tan solid after chromatography. Recrystallization from
hexanes gave fine, colorless needles (mp 88-89 °C, lit. mp 88-
89 °C). 1H NMR (300 MHz, CDCl3): 7.59-7.53 (m,4H), 7.43
(t, J ) 7.50 Hz, 2H), 7.36-7.32 (m, 3H), 3.75 (s, 2H), 3.03 (s,
3H), 2.99 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): 170.9,
140.8, 139.6, 134.1, 129.2, 128.7, 127.3, 127.2, 127.0, 40.6, 37.7,
pellet): 1682 cm-1
.
Gen er a l P r oced u r e for Oxin d ole Syn th esis. In the
drybox, Pd(dba)2 (57.5 mg, 0.10 mmol), BINAP (93.4 mg, 0.15
mmol), and sodium tert-butoxide (288 mg, 3.00 mmol) were
combined in a small round-bottom flask. Dioxane (18 mL) was
added, and the flask was sealed with
a septum. After
removing the flask from the box, 2-bromoanilide (2.00 mmol)
was added. The flask was placed in an oil bath at 100 °C until
the starting material was consumed as determined by GC. The
reaction was poured into 50 mL of saturated NH4Cl solution
and extracted (3 × 30 mL) with ether. The combined ether
extracts were washed with brine (50 mL), dried over MgSO4,
and filtered. The solvent was removed under vacuum, and
the resulting crude product was flash chromatographed on
silica gel. The product was eluted with 15% ethyl acetate in
hexanes.
1-Ben zyloxin d ole (10).34,38 Heating of 2-bromo-N-benzyl-
acetanilide 9 (609 mg, 2.00 mmol) at 100 °C for 3 h gave 297
mg (66%) of 10 as a pale yellow oil after chromatography.
Recrystallization from hexanes gave a pale yellow needles (mp
66.5-67, lit. mp 50-52,34 66-67,59 76-77 °C38). 1H NMR (500
MHz, CDCl3): 7.33-7.34 (m, 3H), 7.26-7.30 (m, 2H), 7.19 (t,
J ) 7.75, 7.84 Hz, 1H), 7.03 (t, J ) 7.12, 7.31 Hz, 1H), 6.75 (d,
J ) 7.55 Hz, 1H), 4.94 (s, 2H), 3.65 (s, 2H) ppm. 13C NMR
(125 MHz, CDCl3): 175.3, 144.4, 135.9, 128.8, 127.9, 127.7,
127.4, 124.5, 124.5, 122.5, 109.2, 43.8, 35.8 ppm. FTIR (neat,
NaCl plate): 1717 cm-1. Anal. Calcd for C15H13NO: C, 80.68;
H, 5.87; N, 6.27. Found: C, 80.59; H, 5.92; N, 6.16.
35.6 ppm. FTIR (KBr pellet): 1633 cm-1
16H17NO: C, 80.30; H, 7.16; N, 5.85. Found: C, 80.03; H,
7.01; N, 5.71.
. Anal. Calcd for
C
N,N-Dim eth yl-2-(4-tolyl)a ceta m id e (2d ).23 4-Bromotolu-
ene (0.25 mL, 2.04 mmol) and DMA (0.20 mL, 2.15 mmol) were
heated at 100 °C for 1.5 h to give 271 mg (75%) of 2d as a
yellow oil after chromatography. Recrystallization from hex-
anes gave colorless needles which melted at approximately
room temperature (lit. mp 24-25 °C). 1H NMR (300 MHz,
CDCl3): 7.13 (brs, 4H), 3.67 (s, 2H), 2.98 (s, 3H), 2.95 (s, 3H),
2.32 (s,3H) ppm. 13C NMR (125 MHz, CDCl3): 171.2, 136.1,
131.9, 129.2, 128.5, 40.5, 37.6, 35.5, 20.9 ppm. FTIR (KBr
pellet): 1640 cm-1. Anal. Calcd for C11H15NO: C, 74.54; H,
8.53; N, 7.90. Found: C, 74.80; H, 8.63; N, 7.88.
1-Meth yloxin d ole (13).34,60,61 Heating 2-bromo-N-methyl-
acetanilide 12 (466 mg, 2.04 mmol) at 100 °C for 2 h gave 186
mg (62%) of 13 as a pale yellow oil after chromatography.
Recrystallization from hexane gave pale orange needles (mp
(58) Felix, D.; Gschwend-Steen, K.; Wick, A. E.; Eschenmoser, A.
Helv. Chim. Acta 1969, 52, 1030-1042.
(59) Cornforth, J . W.; Cornforth, R. H.; Dalgliesh, C. E.; Neuberger,
A. Biochem. J . 1951, 48, 591-597.
N,N-Dim eth yl-2,2-d i(4-tolyl)a ceta m id e (3d ).23 4-Bro-
motoluene (0.25 mL, 2.04 mmol) was coupled with DMA (0.93
(60) Hodges, R.; Shannon, J . S.; J amieson, W. D.; Taylor, A. Can.
J . Chem. 1968, 46, 2189-2194.
(61) Dobrowolski, F.; Stefaniak, L.; Webb, G. A. J . Mol. Struct. 1987,
160, 319-325.
(57) Crundwell, E. J . Chem. Soc. 1956, 368-371.

Pd-Catalyzed R-Arylation of Amides
J . Org. Chem., Vol. 63, No. 19, 1998 6553
86.5-87 °C, lit. mp 86-87 °C). 1H NMR (500 MHz, CDCl3):
7.25-7.20 (m, 2H), 7.02 (t, J ) 7.66, 7.25 Hz, 1H), 6.80 (d, J
) 8.05 Hz, 1H), 3.50 (s, 2H), 3.19 (s, 3H) ppm. 13C NMR (125
MHz, CDCl3): 175.0, 145.2, 127.8, 124.5, 124.3, 122.3, 108.0,
35.7, 26.1 ppm. FTIR (neat, NaCl plate): 1701 cm-1. Anal.
Calcd for C9H9NO: C, 73.45; H, 6.16; N, 9.51. Found: C,
73.52; H, 6.01; N, 9.25.
142.6, 135.8, 127.6, 122.4, 122.2, 107.9, 44.1, 26.1, 24.3 ppm.
FTIR (neat, NaCl plate): 1710, cm-1. Anal. Calcd for C11H13
-
NO: C, 75.40; H, 7.48; N, 7.99. Found: C, 75.30; H, 7.29; N,
7.83.
1-Meth yl-3-sp ir ocycloh exyloxin d ole (21).64 Heating of
N-(2-bromophenyl)-N-methylcyclohexanecarboxamide 20 (595
mg, 2.01 mmol) at 100 °C for 4 h gave 356 mg (82%) of 21 as
a viscous, pale yellow oil after chromatography. 1H NMR (500
MHz, CDCl3): 7.46 (d, J ) 7.23, 1H0, 7.28 (t, J ) 7.70 Hz,
1H), 7.49 (t, J ) 7.56 Hz, 1 H), 6.85 (d, J ) 7.73 Hz, 1H), 3.21
(s, 3H), 1.98-1.92 (m, 2H), 1.88-1.81 (m, 2H), 1.79-1.71 (m,
4H), 1.69-1.61 (m, 1H), 1.59-1.55 (m, 2H) ppm. 13C NMR
(125 MHz, CDCl3): 180.6, 142.8, 135.4, 127.4, 123.8, 121.9,
107.8, 47.4, 33.0, 26.1, 25.2, 21.2 ppm. FTIR (neat, NaCl
plate): 1711 cm-1. Anal. Calcd for C14H17NO: C, 78.10; H,
7.90; N, 6.50. Found: C, 77.87; H, 7.83; N, 6.35.
1-Meth yl-3-p h en yloxin d ole (15).62 Heating of N-(2-bro-
mophenyl)-N-methyl-2-phenylacetamide (615 mg, 2.02 mmol)
at 100 °C for 10 h gave 15 (296 mg, 66%) as pale yellow needles
after chromatography. Recrystallization from hexanes gave
colorless, fine needles (mp 119.5-120 °C, lit. mp 119-120 °C).
1H NMR (500 MHz, CDCl3): 7.36-7.32 (m, 3H), 7.30-7.29 (m,
1H), 7.222-7.21 (m, 2H), 7.18 (d, J ) 7.35 Hz, 1H), 7.07 (t, J
) 7.47 Hz, 1H), 6.91 (d, J ) 7.94 Hz, 1H), 4.62 (s, 1H), 3.26 (s,
3H) ppm. 13C NMR (125 MHz, CDCl3): 176.0, 144.5, 136.6,
128.8, 128.4, 127.5, 125.0, 122.7, 108.1, 52.0, 26.4 ppm. FTIR
(KBr pellet) 1705 cm-1. Anal. Calcd for C15H13NO: C, 80.68;
H, 5.87; N, 6.27. Found: C, 80.52; H, 5.82; N, 6.05.
5-Meth oxy-1,3,3-tr im eth yloxin d ole (23).65 Heating of
N-(2-bromo-4-methoxyphenyl)-N-methylisobutyramide 22 (583
mg, 2.04 mmol) at 100 °C for 12 h gave 350 mg (84%) of 21 as
a viscous, pale yellow oil after chromatography. 1H NMR (500
MHz, CDCl3): 6.84 (d, J ) 2.33 Hz, 1H), 6.80 (dd, J ) 2.22,
7.43 Hz, 1H), 6.76 (d, J ) 8.71 Hz, 1H), 3.81 (s, 3H), 3.20 (s,
3H), 1.37 (s, 6H) ppm. 13C NMR (125 MHz, CDCl3): 183.9,
156.0, 137.1, 136.0, 111.5, 109.9, 108.1, 55.7, 44.5, 26.2, 24.3
1,3-Dim eth yloxin d ole (17).63 Heating of N-(2-bromophen-
yl)-N-methylpropionamide 16 (495 mg, 2.04 mmol) at 100 °C
for 1.5 h gave 17 (165 mg, 50%) as a yellow oil after
chromatography. Recrystallization from hexanes gave a pale
yellow crystalline material (mp 55-56 °C, lit. mp 54-55 °C).
1H NMR (500 MHz, CDCl3): 7.30 (t, J ) 7.83 Hz, 1H), 7.27
(d, J ) 6.72 Hz, 1H), 7.09 (t, J ) 7.52 Hz, 1H), 6.85 (d, J )
7.78 Hz, 1H), 3.45 (q, J ) 7.54 Hz, 1H), 3.23 (s, 3H), 1.50 (d,
J ) 7.93, 3H) ppm. 13C NMR (125 MHz, CDCl3): 178.6, 143.9,
130.6, 127.8, 123.4, 122.3, 107.9, 40.5, 26.1, 15.3 ppm. FTIR
(KBr pellet): 1712 cm-1. Anal. Calcd for C10H11NO: C, 74.50;
H, 6.88; N, 8.69. Found: C, 74.20; H, 6.72; N, 8.39.
ppm. FTIR (neat, NaCl disk): 1709 cm-1
.
5-Cya n o-1,3,3-tr im eth yloxin d ole (25). Heating of N-(2-
bromo-4-cyanophenyl)-N-methylisobutyramide 24 (567 mg,
2.02 mmol) at 100 °C for 4 h with 10 mol % of Pd(dba)2 and 15
mol % BINAP gave 338 mg (84%) of 21 as an orange solid after
chromatography. Recrystallization from hexanes gave light
orange needles (mp 138-139 °C). 1H NMR (500 MHz,
CDCl3): 7.61 (dd, J ) 1.82, 8.08 Hz, 1H), 7.46 (d, J ) 1.18 Hz,
1H), 6.92 (d, J ) 8.08 Hz, 1H), 3.26 (s, 3H), 1.40 (s, 6H) ppm.
13C NMR (125 MHz, CDCl3): 180.8, 146.5, 136.7, 133.1, 125.7,
119.2, 108.4, 105.6, 44.0, 26.4, 24.1 ppm. FTIR (KBr pellet):
1,3,3-Tr im eth yloxin d ole (19).38,63 Heating of N-(2-bro-
mophenyl)-N-methylisobutyramide (524 mg, 2.05 mmol) at 100
°C for 3 h gave 19 (286 mg, 80%) as a yellow oil after
chromatography. Recrystallization from hexanes gave pale
yellow needles (mp 54-55 °C, lit. mp 49-50 °C63). 1H NMR
(500 MHz, CDCl3): 7.24-7.28 (m, 1H), 7.20 (d, J ) 7.37 Hz,
1H), 7.06 (t, J ) 7.69, 7.23 Hz, 1H), 6.84 (d, J ) 7.77 Hz, 1H),
3.22 (s, 3H), 1.33 (s, 6H). 13C NMR (125 MHz, CDCl3): 181.3,
2218, 1716 cm-1
. Anal. Calcd for C12H12N2O: C, 71.98; H,
6.04; N, 13.99. Found: C, 72.14; H, 5.94; N, 13.61.
J O980611Y
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